A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase

Z. X. Xu, J. Liang, V. Haridas, A. Gaikwad, F. P. Connolly, Gordon Mills, J. U. Gutterman

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Avicins, a family of plant triterpene electrophiles, can trigger apoptosis-associated tumor cell death, and suppress chemical-induced carcinogenesis by its anti-inflammatory, anti-mutagenic, and antioxidant properties. Here, we show that tumor cells treated with benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro- methylketone, an apoptosis inhibitor, and Bax-/- and Bak-/- apoptosis-resistant cells can still undergo cell death in response to avicin D treatment. We demonstrate that this non-apoptotic cell death is mediated by autophagy, which can be suppressed by chloroquine, an autophagy inhibitor, and by specific knockdown of autophagy-related gene-5 (Atg5) and Atg7. Avicin D decreases cellular ATP levels, stimulates the activation of AMP-activated protein kinase (AMPK), and inhibits mammalian target of rapamycin (mTOR) and S6 kinase activity. Suppression of AMPK by compound C and dominant-negative AMPK decreases avicin D-induced autophagic cell death. Furthermore, avicin D-induced autophagic cell death can be abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMPK to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicin D. These findings indicate the therapeutic potential of avicins by triggering autophagic cell death.

Original languageEnglish (US)
Pages (from-to)1948-1957
Number of pages10
JournalCell Death and Differentiation
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

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AMP-Activated Protein Kinases
Autophagy
Cell Death
Sirolimus
Apoptosis
Ribosomal Protein S6 Kinases
Triterpenes
Tuberous Sclerosis
Chloroquine
Aspartic Acid
Protein Kinase C
avicin D
Neoplasms
Carcinogenesis
Anti-Inflammatory Agents
Antioxidants
Adenosine Triphosphate
Genes

ASJC Scopus subject areas

  • Cell Biology

Cite this

A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. / Xu, Z. X.; Liang, J.; Haridas, V.; Gaikwad, A.; Connolly, F. P.; Mills, Gordon; Gutterman, J. U.

In: Cell Death and Differentiation, Vol. 14, No. 11, 01.11.2007, p. 1948-1957.

Research output: Contribution to journalArticle

Xu, Z. X. ; Liang, J. ; Haridas, V. ; Gaikwad, A. ; Connolly, F. P. ; Mills, Gordon ; Gutterman, J. U. / A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. In: Cell Death and Differentiation. 2007 ; Vol. 14, No. 11. pp. 1948-1957.
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abstract = "Avicins, a family of plant triterpene electrophiles, can trigger apoptosis-associated tumor cell death, and suppress chemical-induced carcinogenesis by its anti-inflammatory, anti-mutagenic, and antioxidant properties. Here, we show that tumor cells treated with benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro- methylketone, an apoptosis inhibitor, and Bax-/- and Bak-/- apoptosis-resistant cells can still undergo cell death in response to avicin D treatment. We demonstrate that this non-apoptotic cell death is mediated by autophagy, which can be suppressed by chloroquine, an autophagy inhibitor, and by specific knockdown of autophagy-related gene-5 (Atg5) and Atg7. Avicin D decreases cellular ATP levels, stimulates the activation of AMP-activated protein kinase (AMPK), and inhibits mammalian target of rapamycin (mTOR) and S6 kinase activity. Suppression of AMPK by compound C and dominant-negative AMPK decreases avicin D-induced autophagic cell death. Furthermore, avicin D-induced autophagic cell death can be abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMPK to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicin D. These findings indicate the therapeutic potential of avicins by triggering autophagic cell death.",
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